Abstract
PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptation, Physiological / genetics
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Animals
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Appetite Regulation / genetics
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Basal Ganglia Diseases / genetics
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Basal Ganglia Diseases / metabolism
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Basal Ganglia Diseases / pathology
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Brain / metabolism*
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Brain / physiopathology
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Corpus Striatum / physiopathology
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Energy Metabolism / genetics*
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Gene Expression Regulation / genetics
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Gluconeogenesis / genetics*
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Glucose / metabolism
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Hepatocytes / metabolism
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Homeostasis / genetics
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Hyperkinesis / genetics*
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Hyperkinesis / pathology
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Hyperkinesis / physiopathology
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Liver / metabolism
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Liver / physiopathology
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Mice
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Mice, Knockout
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Mitochondria / genetics
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Mitochondria / metabolism*
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / pathology
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Neurons / metabolism
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Obesity / genetics
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Obesity / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Trans-Activators / deficiency
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Trans-Activators / genetics*
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Transcription Factors
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Up-Regulation / genetics
Substances
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CCAAT-Enhancer-Binding Protein-beta
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Trans-Activators
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Transcription Factors
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Glucose